Substituted 6,7 dihydro-1-oxo N(1H-tetrazol-5-yl)-1H,5H-benzo{8 ij{9 quinolizine carboxamides

ABSTRACT

Compounds of the general formula (I):   and pharmaceutically acceptable salts thereof in which: R1 represents a hydrogen atom, an alkyl group, or the group OR3 where R3 is a hydrogen atom or an acyl group, or an alkenyl group or an alkyl group which alkyl group may optionally be substituted by amino, alkylamino, dialkylamino, alkylaralkylamino, aryl, aryloxy, acyloxy, alkoxy, hydroxy or tetrahydropyranyloxy groups; and up to 3 groups R1, which may be the same or different, are present; and R2 represents a hydrogen atom or an alkyl group. The compounds have utility for the treatment of conditions in which combination of an antigen with a reaginic anitbody is primarily responsible.

United States Patent [191 Ellis et al.

[ NOV. 4, 1975 [73] Assignee: Allen & Hanburys Limited, London,

England 22 Filed: Mar.27, 1974 21 Appl. No.: 455,071

[30] Foreign Application Priority Data Apr. 5, 1973 United Kingdom 16279/73 [52] US. Cl. 260/287 P; 260/287 T; 424/258 [51] Int. Cl. C071) 215/16 [58] Field of Search 260/287 R [56] References Cited UNITED STATES PATENTS 3,728,350 4/1973 Beck 260/287 P 3,793,328 2/1974 Hester 260/287 P Primary Examiner-Richard J. Gallagher Assistant Examiner-David E. Wheeler Attorney, Agent, or Firm-Bacon & Thomas [57] ABSTRACT Compounds of the general fomiula (I):

CONH\ N N/ (I H and pharmaceutically acceptable salts thereof in which: R represents a hydrogen atom, an alkyl group, or the group 0R where R is a hydrogen atom or an acyl group, or an alkenyl group or an alkyl group which alkyl group may optionally be substituted by amino, alkylamino, dialkylamino, alkylaralkylamino, aryl, aryloxy, acyloxy, alkoxy, hydroxy or tetrahydropyranyloxy groups; and up to 3 groups R which may be the same or different, are'present; and R represents a hydrogen atom or an alkyl group. The compounds have utility for the treatment of conditions in which combination of an antigen with a reaginic anitbody is primarily responsible.

18 Claims, No Drawings SUBSTITUTED 6,7 DIHYDRO-I-OXO N(1H-TETRAZOL-5-YL)-lH,5H-BENZO[IJ]- QUINOLIZINE CARBOXAMIDES This invention relates to certain novel benzoquinolizines which have been found to have a useful profile of pharmocological activity. It also relates to a process for the production thereof, to pharmaceutical compositions containing them and to their use in therapy.

The invention provides compounds of the general formula (I) below and pharmaceutically acceptable salts thereof.

in which: R represents a hydrogen atom, an alkyl group, or the group R where R is a hydrogen atom or an acyl group, or an alkenyl group or an alkyl group which alkyl group may optionally be substituted by amino, alkylamino, dialkylamino, alkylaralkylamino, aryl, aryloxy, acyloxy, alkoxy, hydroxy or tetrahydropyranyioxy groups; and up to 3 groups R which may be the same or different, are present; and R represents a hydrogen atom or an alkyl group.

The term alkyl when used above to define a single group or part of a group refers to a straight or branched chain alkyl group containing from 1 to 6 carbon atoms preferably 1 to 4 carbon atoms. The term alkenyl means a straight or branched chain alkenyl group containing from 3 to 6 carbon atoms and the term aryl preferably means phenyl. The term acyl when used above preferably means alkanoyl and includes the formyl and trifluoroacetoxy groups. Our preferred classes of compounds are those in which the following groups have the meanings given.

below:

- R hydrogen, alkyl particularly isopropyl, hydroxy,

2 ganic bases such as dimethylaminoethanol. Where basic groups are present addition salts may also be formed with organic or inorganic acids e.g. hydrochloric acid.

The compounds of the invention show promise as agents for the treatment of conditions in which combination of an antigen with a reaginic antibody is primarly responsible, for example extrinsic asthma, hay fever, urticaria, eczema or atopic dermatitis. Thus 6-7- dihydrol -oxo-N( 1H-tetrazol-5-yl-)- l H,5H-benzo(ij) quinolizine-Z-carboxamide (Example I) was compared with disodium cromoglycate, which is known to be effective in the prophylactic treatment of asthma. It was shown to be about 10 times as active as disodium cromoglycate in inhibiting release of histamine in the passive peritoneal anaphylaxis induced in rats with the DNP egg albumen system (J. Exp. Med. 1969, 127, 727).

The invention also provides pharmaceutical compositions which contain a compound of general formula (I) or a salt thereof together with a pharmaceutically acceptable carrier, excipient, or other formulatory agent. The compositions may also contain supplementary medicinal agents, e.g. bronchodilators. Suitable forms of oral administration include tablets, capsules, syrups, or emulsions. For administration by inhalation the compositions according to the invention may be in the form of a powder or snuff or as an aerosol spray presentation. The latter may conveniently be a pressurised pack with a metering valve to deliver a fixed dosage unit or may be an aqueous solution delivered via a nebuliser.

The dosage at which the active ingredient is adminis- (III) In the above formula (II) R, and R have the meanings given above or are groups convertible thereto.

The condensation of an acid (H) with S-aminotetrazole (III) may be effected with the aid of a variety of 3 methylformamide. The reaction may be carried out at ambient or elevated temperatures e.g. 20120C.

Suitable activated derivatives of 1 the benzo('ij) quinolizinocarboxylic acids (11) include the acid halide,

preferably the acid chloride or a mixed anhydride preferably the mixed anhydride derived from an acid (II) and: an alkylcarbonic acid e.g. ethylcarbonic acid C H OCOOH.

The condensation of-an acid chloride derived from a :'benzo(ij)quinolizine-Z-carboxylic acid (11) with 5- aminotetrazole is preferably carried out in an aprotic solvent (such as dioxan or tetrahydrofuran, and is also preferably carried out in the presence of an acid acceptor, for example a tertiary organic base, such as pyridine, or triethylamine, or in an aqueous medium in the presence of an inorganic base such as an alkali metal hydroxide, carbonate or bicarbonate e.g. sodium or potassium hydroxide, sodium or potassium carbonate or bicarbonate.

When a mixed anhydride is used'as activated derivative the reaction may also be carried out in a polar aprotic solvent such as dimethylformamide, at a reaction temperature which is preferably below C.

Compounds according to the invention may also be converted into other compounds of the invention. Thus compounds in which R is a benzyloxy group may be converted into compounds in which R is a hydroxy group by hydrogenolysis, for example by reaction with hydrogen in the presence of a noble metal catalyst such as palladium. Compounds in which R is a tetrahydropyranyloxyalkoxy group may be converted into compounds in which R is a trifluoroacetoxyalkoxy group by treatment with trifluoroacetic acid. Compunds in which R; is a hydroxyalkoxy group may be prepared by hydrolysis, preferably alkaline hydrolysis, of the compounds of formula (I) where R, is a trifluoroacetoxyalkoxy group.

The starting benzo(ij)quinolizine-Z-carboxylic acids (11) may be prepared from the tetrahydroquinoline (IV) by treatment with an alkyl alkoxymethylenema- 4 the intermediate ester (V1) with polyphosphoric acid, followed if necessary by hydrolysis of the b'en'zo (ij) quinolizine 2-carboxylic acid ester (VII) with aqueous alkali.

lonate (V), where R and R alkyl, and cyclisation of The groups R and R may be present throughout the synthesis of the compounds of formula (II) or maybe introduced or modified at any convenient stage inthe synthesis. For example the benzo(ij)quinoliiine-2-carboxylic acid (II; R 0R where R has the meanings given other than hydrogen, may be converted into the corresponding acid (II, R OH) by heating with aqueous hydrogen bromide in glacial acetic acid. The hydroxy acid (H; R OH) may then be converted into other benzo(ij )quinolizine-2-carboxylicacids (ll; R,

0R by standard alkylation or acylation procedures. For example the acid (II; R 0R may be prepared by the reaction of the hydroxy acid (II; R OH) with conventional alkylating agents such as an alkyl halide or dialkyl sulphate. These reactions may be advantageously carried out in a solvent such as 2-butanone or dimethylformamide and in the presence of an alkali metal carbonate such as potassium carbonate; the reaction may be carried out at elevated temperatures if desired.

The following Examples illustrate the invention:

EXAMPLE 1 6,7-Dihydro'-1-oxo- N( ll-l-tetrazol-5-yl)-lH,5l-l-benzo[ij]-quinolizine-2-carboxamide 6,7-Dihydrol-oxo- 1 H ,5H-benzo[ij ]quinolizine-2- carboxylic acid (2 g) and N,N'-carbony1diimidazole- (1.4 g) in dimethylformamide (40 ml) were heated to for 5 /2 hours. S-Amino-ll-l-tetrazole (1.1 g) was added and the mixture was heated to. 100 for 1 hour.

The precipitate was collected and dissolved in a mixture of dimethylaminoethanol, water and dimethylformamide (1:111). The solution was filtered and aciditied with dilute hydrochloric-acid and the solid was collected and dried, m.p. above 318 ((1), (60%). v

EXAMPLE 2 6,7-Dihydro-9-methox'yl-oxo-N( lH-tetrazol-5-yl)- lH,5H'-benzo [ij ]quinolizine-Zcarboxamide 6,7-Dihydro-9-methoxyl-oxo- 1 H,5H-benzo[ij]quinolizine-2-carboxylic acid (0.8 g) and N,N'- carbonyldiimidazole (0.75 g) in tetrahydrofuran (15 ml) and dimethylformamide (15 ml) were heated under reflux for 6 hours. S-Amino-lH-tetrazole (0.8 g) was added and the mixture was heated under reflux for 30 minutes. The solid was collected and dissolved in aqueous dimethylaminoethanol ml, 5%) and the solution was filtered and acidified with glacial acetic acid. The solid was collected, washed with hot ethanol and dissolved in aqueous dimethylaminoethanol (10 ml, 5%). The solution was acidified with glacial acetic acid and the solidwas filtered off, m.p. 321322 (d), (50%).. 0

EXAMPLE 3 9-Ethoxy6,7-dihydrol -oxo-N( 1H-tetrazol-5-yl)- 1H,5H-benzo [ij]quinolizine-Z-carboxamide a. 6,7-Dihydro-9-hydroxy- 1 -oxo- 1H,5H-benzo[ij]quinolizine-2-carboxylic acid 6,7-Dihydro-9-methoxyl-oxo-l H.5H-benzo[ij]quinolizine-Z-carboxylic acid (200 mg), aqueous hydrobromic acid (2 ml, 48%) and glacial acetic acid (2 ml) were heated under reflux to 19 hours and allowed to cool. The solid was collected, m.p. 338 (d),

b. l 9-Ethoxy-6, 7-dihydrol-oxo-1H,5H benzo[ij]quinolizine-2-carboxylic acid 6,7-Dihydro-9-hydroxy- 1 -oxo- 1 H,5H-benzo[ij]- quinolizine-Z-carboxylic acid (3.6 g), diethyl sulphate (5.8 ml) and anhydrous potassium carbonate (8.1 g) in dimethylformamide (180 ml) were stirred and heated to 100 for hours. The solid was filtered off and the filtrate was evaporated. The residue (9 g), aqueous sodium hydroxide (50 ml, 2N) and ethanol (150 ml) were heated under reflux for 45 minutes. The mixture was cooled and acidified with dilute hydrochloric acid. The solid was collected, dried and crystallised from dimethylformamide,'m.p. 233235, (60%).

The following compounds were prepared in a similar manner from 6,7-dihydro-9-hydroxy-l-oxo-1H,5H- benzo[ij]quinolizine-Z-carboxylic acid using the alkylating agent quoted in the brackets:

2. 6,7-dihydro-9-( 2-hydroxyethoxy)- l-oxo-1H,5H- benzo [ij]quinolizine-Z-carboxylic acid, m.p. (2- bromoethanol).

3 9-(2Ethoxyethoxy)-6,7-dihydro-loxo-1H,5H- benzo [ij ]quinolizine-2-carboxylic acid, m.p. l77 l79, (66%) (2-ethoxyethyl bromide).

4. 6,7-Dihydro-1-oxo-9-[2 2 -tetrahydropyranyloxy) ethoxy]- 1H,5H-benzo[ij ]quinolizine- 2-carboxylic acid, m.p. l45.5.l46.5, (84%) (2- (2'- tetrahydropyranyloxy)ethyl bromide).

5. 6,7-Dihydro-9-isoproproxy l-oxol l-LSH-benzo[ij]quinolizine-Z-carboxylic. acid, mp. 23023-l, (35%) (isopropyl bromide). 5

c. 9-Ethoxy-6,7-dihydro1-oxo-N( lH-tetrazol-S-yl 1H,5H-benzo[ij]quinolizine-2-carboxamide 9-Ethoxy-6,7- dihydrob l-oxo-IH, SH-benzo[ij]quinolizine-2-carboxylic acid (200 mg) and N,N'- carbonyl-diimidazole ([31 mg) in dimethylformamide (5 ml) were heated at 100 for 6 hours. S-Amino-IH- tetrazole (75 mg) was added and the mixture was heated at 100 for 1 hour and cooled. The solid was collected and dissolved in warm (60) aqueous potassium hydroxide (20 ml, 1N) and the solution was filtered and acidified with dilute hydrochloric acid. The solid was collected and dried, m.p. 3143l5.5 (d), (46%).

The following compounds were prepared in a similar manner (using S-aminb-lH-tertrazole and the indicated starting material):

9-( 2-Ethoxyethoxy)-6 ,7-dihydro- 1 -oxo-N( lH-tetrazol-5-yl)-1H,5H-benzo[ij]quinolizine-2-carboxamide, m.p. 286-288, (43%) (9-( 2-Ethoxyethoxy)- 6,7-dihydrol-oxol H,5H-b'enzo[ij ]quinolizine-Z'carboxylic acid).

6,7-Dihydrol-oxo9- [2 2 -tetrahydropyranyloxy) ethoxy]-N( 1H-tetrazol-5-yl)-1H,5H-benzo[ij]quinoli- Zine-2-carboxamide, m.p. 300 (d), (30%) (6,7-Dihy dro- 1-oxo-9-[2 2 "-tetrahydropyranyloxy )ethoxy] lH,5H-benzo[ij] quinolizine-Z-carboxylic acid). 6,7- Dihydro- 9-isopropoxy-1 -oxo-N( lH-tetrazol-S-yl 1H,5H-benzo[ij]quinolizine-2-carboxamide, m.p. 300", (47%) (6,7-Dihydro-9-isopropoxy-l-oxo- 1H,5 H-benzo[ij ]quinolizine-Z-carboxylic acid).

EXAMPLE 4 9-Allyloxy-6,7dihydro-1-oxo-N( lH-tetrazol-S -yl ll-l,5 H-benzo [ij ]quinolizine-Z-carboxamide zine-2-carboxylic acid, allyl ester b. 1 9-Allyloxy-6,7-dihydro l -oxol H,5H-benzo[ij] quinolizine-2-carboxylic acid 9-Allyloxy-6,7-dihydrol-ox.o-'lH,5H-benzo[ij] quinolizine-2-carboxylic acid, allyl ester (2.4g), N sodium hydroxide (8.8 ml) and ethanol (8.9 ml) were heated on a steam bath for 0.5 hours. The ethanol was distilled ofi and 2N hydrochloric acid was added to the remaining aqueous solution. The solid was collected and dried. It had m.p. 205206.5,

The following compound was prepared in a similar manner:

2. 9-Berizyloxy-6,7-dihydro-l-oxo-1H,5H-benzo [ij] quinolizine-Z-carboxylic acid, m.p. 233235, (81%), from the compound of (a)(2) above.

c. 1. 9-Allyloxy-6,7-dihydro- 1 -oxo-N( 1 H-tetrazol-S-yl 1 H ,SH-benzo ij ]quinolizine-2-carboxamide EXAMPLE 5 6,7-Dihydro-9-( 2-dimethylaminoethoxy)- 1-oxo-N( 1H- tetrazol-5-yl)-1H,5H-benzo[ij]quinoliZine-2-carboxamide, hydrochloride a. 1. 6,7-Dihydro-9-( 2-dimethylaminoethoxy 1 -oxo- 1 H,5H-benzo[ij ]quinolizine-2-carboxylic acid, hydrochloride 6,7-Dihydro-9-hydroxy- 1 -oxo- 1 H,5 H-benzo[ij] quinolizine-Z-carboxylic acid (2 g), Z-diemthylaminoethyl chloride, hydrochloride (3.5 g) and potassium carbonate (5.6 g) in dimethylformamide (100 ml) were stirred and heated at 100 for 30 hours. The mixture was filtered and the filtrate was evaporated. The residue in N sodium hydroxide (10 ml) and ethanol (10 ml) was heated under reflux for 35 minutes and cooled. 2N Hydrochloric acid was added and the solid was collected and dried. It had m.p. 277279 (d), (40%).

2. 9-[2-(N-benzyl-N-methylamino)ethoxy]-6,7-dihydrol-oxo- 1 H,5H-benzo[ij ]quinolizine carboxylic acid, hydrochloride, monohydrate, m.p. 240 (d), (34%), was prepared in a similar manner from N-benzyl-N- methylaminoethyl bromide and 6.7-dihydro-9- hydroxy-1-oxo-ll-l,5H-benzo[ij]quinolizine-2-carboxylic acid.

b. l. 6,7-Dihydro-9-( Z-dimethylaminoethoxy 1 -oxo-N( 1 H- tetrazol-S-yl 1H,5H-benzo[ ij ]q'uinolizine-2-carboxamide, hydrochloride, dihydrate 6,7-Dihyd ro-9a( Z-dimethylaminoethoxy 1 -oxoll-l,5H-benzo[ij]quinolizine-Z-carboxylic acid, hydrochloride 1.1 g) and N,N-carbonyldiimidazole (1 g) in dimethylformamide (55 ml) were stirred and heated at 100 for 4 hours. The solution was filtered and 5- amino-ll-l-tetrazole (1 g) was added to the filtrate and the mixture was stirred and heated at 100 for 1 hour. The solid that crystallised was collected and dissolved in 2N sodium hydroxide. 2N Hydrochloric acid was added to the solution and the solid was collected and was crystallised from glacial acetic acid and recrystallised from a mixture of dimethylformamide, isoprop'anol and water. It had m.p. 272274,

2. 9-[Z-N-Benzyl-N-methylamino)ethoxy]-6,7-dihydro-1-oxo-N( lH-tetrazol-5-yl)-1H,5H-benzo[ij]- quinolizine-2-carboxamide, hydrochloride monohydrate, m.p. 239-242 (d), (24%) was prepared in .a similar manner from the corresponding aciddescribed in Example 5(a)(2) above.

EXAMPLE 6 6,7-Dihydrol -oxo-N( 1H-tetrazol-5yl)-9-[2 '-(trifluoroacetoxy )ethoxy]- ll-l,5H-benzo[ij ]quinolizine-2- carboxamide 6,7-Dihydro-1-oxo-N( lH-tetrazol-5-yl)-9-[ 2 '-(2 tetrahydropyranyloxy)ethoxy]-1H,5 l-l-benzo ij quinolizine-2-carboxamide (Example 3(c) (0.7 g), trifluoroacetic acid (50 ml) and water (5 ml) were stirred at room temperature for 3 hours. The mixture was evaporated and the residue was triturated with water to give a solid which was collected and dried, m.p. 300 ((1), (84%).

EXAMPLE 7 6,7-Dihydro 9-(2-hydroxyethoxy)- 1 -oxo-N( lH-tetrazol-Syl 1 l-l,5H-benzo[ij ]quinolizine 2-carboxamide 6,7-Dihydrol -oxo-N( 1H-tetrazol-5-yl)-9-[2 '-(trifluoroacetoxy)ethoxy]- lH-5l-l-benzo[ ij]quinolizine-2- carboxamide (0.4 g) in N sodium hydroxide (15 ml) was stirred at room temperature for 3 hours. The solution was filtered and the filtrate was acidified to give a solid that was crystallised from dimethylformamide, m.p. 295 (d), (64%).

EXAMPLE 8 9-Benzyloxy-6,7-dihydrol-oxo-N( lH-tetrazol-5-yl)- 1H,5H-benzo[ij ]quinolizine-2-carboxamide, sodium salt 9-Benzyloxy-6,7-dihydro-1-oxo-N( lH-tetrazol-5-yl)- ll-l,5l-l-benzo[ ij ]quinolizine-Z-carboxamide (Example 4(c) (2) (0.5 g) was dissolved in aqueous dimethylaminoethanol and 2N sodium carbonate was added. The solid that was precipitated was collected and dried. It had m.p. 300 (d).

EXAMPLE 9 6,7-Dihydro-5-methyl- 1 -oxo-N( 1l-l-tetrazol-5-yl)- 1 H ,5 H-benzo[ ij ]quinolizine-Zcarboxamide 6,7-Dihydro-5-methyll-oxolH,5H-benzo ij] quinolizine-Z-carboxylic acid (4.5 g) and N,N-carbonyldiimidazole (3 g) in dimethylformamide (50 ml) were stirred and heated to for 3 hours. S-Aminoll-l-tetrazole (1.57 g) was added and the mixture was stirred and heated to 90 for a further 2 hours. The solid was collected and dried. It had m.p. 308 ((1), (75%).

EXAMPLE 1O 6,7-Dihydro-9-isopropyll-oxo-N( l H-tetrazol-5-yl)- 1l-l,5 l-l-benzo [ij ]quinolizine-2-c arboxamide a. 1,2,3,4-Tetrahydro-6-isopropylquinoline 6-Isopropylquinoline (12.4 g) and copper chromite catalyst 1.3 g) in ethanol (70 ml) were stirred in an atmosphere with hydrogen at 2000 psi. pressure and a temperature of for 2 hours. The catalyst was filtered off, the filtrate was evaporated and the residue was'distilled under reduced pressure. The fraction that distilled at 102103/0.45 mm was collected, 47%.

b. 1,2,3 ,4-Tetrahydro- 6isopropylquinol-1-yl)methylene]-malonic acid, diethyl ester 1,2,3,4-Tetrahydro-6-isopropylquinoline (8.5 g) and diethyl ethoxymethylenemalonate (10.5 g) were stirred and heated to 120-l40 for 1 hour. The mixture crystallized on cooling and the solid was collected. It had m.p. 61-64, (100%). i

c. 6,7-Dihydro-9isopropyl- 1-oxo-lH,5H-benzo[ij] quinolizine-2-carboxylic acid, ethyl ester 1,2,3,4-Tetrahydro-6-isopropylquinoll-yl) methylene]malonic acid, diethyl ester (15.1 g) was added to polyphosphoric acid (44 g) which was heated at 100 and maintained at this temperature for 1 hour. The mixture was cooled and added to water (250 ml) and the solution was neutralised with 5N sodium hydroxide, The solid was filtered off, dried and crystallised from a mixture of ethyl acetate and methanol. It had m.p. 235237, (54%).

d. 6,7-Dihydro-9-isopropyll-oxolH,5H-benzo[ ij quinolizine-Z-carboxylic acid quinolizine-2-carboxylic acid, ethyl ester (6 g) in N sodium hydroxide (22 ml) and ethanol (22 ml) was heated under reflux for 1 hour. The ethanol was distilled off and the residual solution was acidified to pH 1 with hydrochloric acid. The solid that separated was filtered off and was washed with water and dried and crystallised from dimethylformamide. It had m.p. 267-269.5 (92%).

e. 6,7-Dihydro-9-isopropyl- 1-oxo-N( lH-tetrazol-S -yl)- 1H,5H-benzo[ij ]-quinolizine-2-carboxamide 6,7-Dihydro-9-isopropyl-1-oxo-1H,5H-benzo[ij] quinolizine-Z-carboxylic acid (3.3 g) and N,N'-carbonyldiimidazole (2.1 g) in dimethylformamide (50 ml) were stirred and heated to 100 for 3 hours. 5- Amino-lH-tetrazole (1 .15 g) was added and the mixture was stirred and heated at 100 for 3 hours and the solid that separated was collected and crystallised from dimethylsulphoxide. It had m.p. 300 (d), (24%).

EXAMPLE 11 6,7-Dihydro-9-hydroxy-l -oxo-N( 1H-tetrazol-5-y1)- 1H,5H-benzoij ]quinolizine-Z-carboxamide EXAMPLE 12 (pharmaceutical compositions) Inhalation aerosol To prepare 100 aerosol cans, each of which delivers 200 metered doses of 1.0 mg AH 11215 Micronise the AH 11215 sodium salt to give a powder in which nearly all the particles are smaller than Sum in diameter. Dissolve 0.60 g of Emulsifier YN 100** in 570 g of trichlorofluoromethane (Arcton 11) at 10C. Disperse in this solution with a high shear mixer 28.3 g of micronised AH 11215 sodium salt. Meter 5.7 g fractions of the drug suspension into suitable aluminum cans and seals the cans by crimping on suitable pressure-filling aerosol valves capable of metering mg doses of final product. Inject through the valve into each can 14.7 g of dichlorodifluoromethane (Arcton l2). Fit a suitable oral adaptor/actuator unit on to each can.

**Emulsifier YN is a grade of the ammonium salt synthetic lecithin, supplied by Cadbury Bros.

AH11215 is the product of Example 1 and is used in the form of its sodium salt.

Tablets To prepare 10,000 each containing 200 mg AH 11215 Mix together 2.160 kg of AH 11215 sodium salt (sieved 60 mesh) with 2.00 kg, lactose B.P. and 100 g of maize starch. Evenly moisten the mixed powders with sufficient water to produce a cohesive mass, pass this through a 16 mesh sieve and dry the granules at 50C in a fluidised bed dryer. Blend the dry granules with 100 g of maize starch and 10 g magnesium stearate. Compress on a suitable tablet press to give tablets each weighing 440 mg.

Capsules (for oral use) To prepare 10,000 hard gelatin capsules containing AH 11215 Mix the powdered AH 11215 sodium salt (sieved 60 mesh) with sufficient Sta-Rx starch* 1500 and magnesium stearate equivalent to 1% of the total powderweight, to give the required dosage, which can be up to 250 mg AH l 1215. Fill into No. 1 hard gelatin capsules with a suitable capsulating machine. *Sta-Rx starch 1500 is a grade of free-flowing starch supplied by A. E. Staley Co. Ltd., London.

Capsules for Inhalation To prepare 10,000 capsules each containing 20mg AH 1 1215, for use in an insuffiator for inhalation into the lung. I

Micronise the AH 11215 sodium salt to give a powder in which nearly all particles are smaller than Sum diameter. Blend 216 g of micronised drug with 200 g of lactose B.P., previously sieved through 200 mesh and over 300 mesh sieves. Fill the powder blend into No. 3 hard gelatin capsules on a suitable machine, so that each capsule contains 41.6 mg of powder.

AH 11215 may be replaced by another compound according to the invention if desired.

The sodium salt of AH 11215 may be made from the parent carboxamide prepared according to Example 1 by utilizing sodium carbonate as described generally in Example 8.

1 1 We claim: 1. Compounds of the formula (I):

and pharmaceutically acceptable salts thereof in which: R represents a hydrogen atom, an alkyl group, or the group R where R is a hydrogen atom or an alkanoyl group, or an alkenyl group or an alkyl group which alkyl group may be substituted by alkylamino, dialkylamino, alkylbenzylamino, phenyl, benzyl, benzyloxy, alkanoyloxy, alkoxy, hyrdroxy, or tetrahydropyranyloxy groups; and up to 3 groups R which may be the same or different are present; and R represents hydrogen or an alkyl group, wherein alkyl when used above to define a single group or part of a group refers to a straight or branched chain alkyl group containing from 1 to 6 carbon atoms and the term alkenyl as defined above refers to a straight or branched chain alkenyl group containing from 3 to 6 carbon atoms and the term alkanoyl includes the formyl and the trifluoroacetoxy groups.

2. Compounds as claimed in claim 1 in which R is selected from the group consisting of hydrogen, isopropyl, hydroxy, methoxy, ethoxy, isopropoxy, benzyloxy, allyloxy, 2-ethoxyethoxy, 2-hydroxyethoxy, 2-dimethylaminoethoxy, 2-methylbenzylaminoethoxy, trifluoroacetoxy, and 2-(tetrahydropyranyloxy)-ethoxy; R is hydrogen or methyl. 7

3. Compounds as claimed in claim 1 in which R represents hydrogen or alkyl. I

4. A compound as claimed in claim 1 which is 6,7- dihydrol -oxo-N( l H-tetrazol--yl)-1H,5 l-l-benzo[ ij quinolizine-Z-carboxamide.

5. A compound as claimed in claim 1 which is 6,7- dihydro-9-methoxy- 1-oxo-N( lH-tetrazol-Syl l l-l,5l-lbenzo ij quinolizine-2-carboxamide.

6. A compound as claimed in claim 1 which is 9- ethoxy-6,7-dihydro-1-oxo-N( lH-tetrazol-5-yl)- lH,51-lbenzo[ij]quinolizine-2-carboxamide.

7. A compound as claimed in claim 1 which is 9-(2- ethoxyethoxy)-6,7-dihydrol -oxo-N( 1 H-tetrazol-S-yl lH,5H-benzo[ij]quinolizine-2-carboxamide.

8. A compound as claimed in claim 1 which is 6,7- dihydro- 1 -oxo-9- 2 2 -tetrahydropyranyloxy )ethoxy ]N( 1H-tetrazol-5-yl)- 1 l-l,5H-benzo ij quinolizine-Z- carboxamide.

9. A compound as claimed in claim 1 which is 6,7- dihydro-9-isopropoxy- 1 -oxo-N( 1 H-tetrazol-S -yl 1 H,5H-benzo ij ]quinolizine-2-carboxamide.

10. A compound in claim 1 which is 9-allyloxy-6,7- dihydrol -oxo-N( 1H-tetrazol-5-yl)- 1 H,5H-benzo[ij quinolizine-2-carboxamide.

11. A compound as claimed in claim 1 which is 9- benzyloxy-6,7-dihydro- 1-oxo-N( lH-tetrazol-5-yl)- lH,5l-l-ben zo[ ij quinolizine-2-carboxamide.

12. A compound as claimed in claim 1which is 9-[2- (N-benzyl-N-methylamino )ethoxy] -6,7-dihydrol-oxo- N( 1H-tetrazol-5-yl)- 1 l-l,5H-benzo[ij]quinolizine-Z- carboxamide, hydrochloride, monohydrate.

13. A compound as claimed in claim 1 which is 6,7- dihydrol -oxo-N( lH-tetrazol-5-yl)-9-[2-(trifluoroacetoxy )ethoxy lH,5H-benzo ij ]quinolizine- 2- carboxamide. v

14. A compound as claimed in claim 1 which is 6,7-dihydro-9-( Z-hydro xyethoxy)- 1-oxo-N( 1l-l-tetrazol-S-yl lH,5l-l-benzo[ ij ]quinolizine-Z-carboxamide.

15. A compound as claimed in claim 1 which is 9- benzyloxy-6,7-dihydro- 1-oxo-N( 1H-tetrazol-5-yl)- 1H,5 H-benzo [ij ]quinolizine-2-carboxamide, sodium salt.

16. A compound as claimed in claim 1 which is 6,7- dihydro-S-methyl- 1 -oxo-N( lH-tetrazol-S-yl lH,5l-lbenzo ij quinolizine-2- carboxamide 17. A compound as claimed in claim 1 which is 6,7- dihydro-9-isopropyl-1-oxo-N( ll-l-tetrazol-5-yl)- 1l-l,5H-benzo[ij]quinolizine-2-carboxamide.

18. A compound as claimed in claim 1 whichis 6,7- dihydro-9-hydroxy-1-oxo-N( 1H-tetrazol-5-yl)-1H,5H-

benzo ij quinolizine-Z-carboxamide. I 

1. COMPOUNDS OF THE FORMULA (I):
 2. Compounds as claimed in claim 1 in which R1 is selected from the group consisting of hydrogen, isopropyl, hydroxy, methoxy, ethoxy, isopropoxy, benzyloxy, allyloxy, 2-ethoxyethoxy, 2-hydroxyethoxy, 2-dimethylaminoethoxy, 2-methylbenzylaminoethoxy, trifluoroacetoxy, and 2-(tetrahydropyranyloxy)-ethoxy; R2 is hydrogen or methyl.
 3. Compounds as claimed in claim 1 in which R2 represents hydrogen or alkyl.
 4. A compound as claimed in claim 1 which is 6,7-dihydro-1-oxo-N(1H-tetrazol-5-yl)-1H,5H-benzo(ij) quinolizine-2-carboxamide.
 5. A compound as claimed in claim 1 which is 6,7-dihydro-9-methoxy-1-oxo-N(1H-tetrazol-5yl)-1H,5H-benzo(ij)quinolizine-2 -carboxamide.
 6. A compound as claimed in claim 1 which is 9-ethoxy-6,7-dihydro-1-oxo-N(1H-tetrazol-5-yl)-1H,5H-benzo(ij)quinolizine-2 -carboxamide.
 7. A compound as claimed in claim 1 which is 9-(2-ethoxyethoxy)-6,7-dihydro-1-oxo-N(1H-tetrazol-5-yl)-1H,5H -benzo(ij)quinolizine-2-carboxamide.
 8. A compound as claimed in claim 1 which is 6,7-dihydro-1-oxo-9-(2''-(2''''-tetrahydropyranyloxy)ethoxy)N(1H-tetrazol-5-yl)-1H,5H-benzo(ij)quinolizine-2-carboxamide.
 9. A compound as claimed in claim 1 which is 6,7-dihydro-9-isopropoxy-1-oxo-N(1H-tetrazol-5-yl)-1H,5H -benzo(ij)quinolizine-2-carboxamide.
 10. A compound in claim 1 which is 9-allyloxy-6,7-dihydro-1-oxo-N(1H-tetrazol-5-yl)-1H,5H-benzo(ij)quinolizine -2-carboxamide.
 11. A compound as claimed in claim 1 which is 9-benzyloxy-6,7-dihydro-1-oxo-N(1H-tetrazol-5-yl)-1H,5H-benzo(ij)quinolizine-2-carboxamide.
 12. A compound as claimed in claim 1 which is 9-(2-(N-benzyl-N-methylamino)ethoxy)-6,7-dihydro-1-oxo-N(1H-tetrazol-5-yl) -1H,5H-benzo(ij)quinolizine-2-carboxamide, hydrochloride, monohydrate.
 13. A compound as claimed in claim 1 which is 6,7-dihydro-1-oxo-N(1H-tetrazol-5-yl)-9-(2''-(trifluoroacetoxy)ethoxy)-1H,5H -benzo(ij)quinolizine-2-carboxamide.
 14. A compound as claimed in claim 1 which is 6,7-dihydro-9-(2-hydroxyethoxy)-1-oxo-N(1H-tetrazol-5-yl)-1H,5H -benzo(ij)quinolizine-2-carboxamide.
 15. A compound as claimed in claim 1 which is 9-benzyloxy-6,7-dihydro-1-oxo-N(1H-tetrazol-5-yl)-1H,5H-benzo(ij)quinolizine-2-carboxamide, sodium salt.
 16. A compound as claimed in claim 1 which is 6,7-dihydro-5-methyl-1-oxo-N(1H-tetrazol-5-yl)-1H,5H-benzo(ij)quinolizine-2 -carboxamide.
 17. A compound as claimed in claim 1 which is 6,7-dihydro-9-isopropyl-1-oxo-N(1H-tetrazol-5-yl)-1H,5H-benzo(ij)quinolizine-2-carboxamide.
 18. A compound as claimed in claim 1 which is 6,7-dihydro-9-hydroxy-1-oxo-N(1H-tetrazol-5-yl)-1H,5H-benzo(ij)quinolizine-2-carboxamide. 